This proposal represents the first competing renewal of Vanderbilt's Gl SPORE. It extends major translational research accomplishments of the previous granting cycle and redirects resources into emerging areas of opportunity identified in SPORE-supported pilot projects. Significant translational research accomplishments made during the first grant cycle include: 1) identification of p120 as a key regulator of E-cadherin biology;2) development of a highly sensitive urinary assay for PGE-M, an established biomarker of eicosanoid pathway activation and a potential biomarker for colonic neoplasia;3) the successful conduct of a clinical trial with biological correlates to evaluate inhibition of EGF receptor (EGFR) signaling and 4) the development of a unique biorepository of colorectal adenomas with matched normal rectal mucosa. This proposal represents a continuation of successful projects and establishment of new projects based on the oversight and recommendations of our External Advisory Board and Institutional Steering Committee. The proposal consists of 4 projects and 5 cores and continues to be focused entirely on colorectal cancer (CRC), the second leading cause of cancer deaths in the United States. Our potential for continued success is high based on 1) productivity during the first funding cycle;2) strong and highly integrated institutional support;3) attraction of promising investigators to the field of Gl cancer through career development and pilot project funding;4) unique imaging, proteomic and high throughput screening with chemical synthesis capabilities;5) a complementary large institutional grant (Mouse Models of Human Cancers Consortium) and initiative (Ayers Institute) focused on the early diagnosis, prevention and treatment of CRC;6) a team of highly interactive clinical investigators and basic scientists positioned in a collegial environment and;7) strong inter-SPORE collaborations as well as pharmaceutical (OSI), national (H. Lee Moffitt Cancer Center) and international (Ludwig Institute).